NRC-AN-019 is a protein-tyrosine kinase inhibitor; it inhibits the abnormal function of BCR-ABL tyrosine kinase, which is produced by the Philadelphia chromosome abnormality and is found in Chronic Myeloid Leukemia (CML). NRC-AN-019 inhibits cell proliferation and induces apoptosis (programmed cell death) in the BCR-ABL cell lines and in the leukemic cells generated by CML. It also acts effectively against other tumors such as head and neck cancer, prostate cancer and the like.
Since the initial discovery of tyrosine-specific protein kinases encoded by the transforming viruses and their normal cellular homologues, there has been a great deal of interest in understanding their role in cancer and exploring their potential as therapeutic targets. BCR-ABL tyrosine kinase inhibitors started an era of molecular targeted therapy and marked a great milestone in cancer drug discovery.
Oral drug administration is the most generally accepted route of administration for treating diseases. The lipophilic drugs exhibit poorer solubility and release rate when administered as conventional tablets or capsules and thus exhibit lower bioavailability. Therefore, in solving the problem of low bioavailability of a poorly soluble drug, improvement of the absorption of the orally administered drug is the key point.
Considering the drug bioavailability and variability in patient dose response, NRC-AN-019 presents specific difficulties in relation to solubility and its formulation development. The inventors of this present application have surprisingly found that lipid-based formulation technology provides a therapeutically effective platform for the delivery of NRC-AN-019 in terms of bioavailability and pharmacological response.
Novel phenylaminopyrimidine derivatives have been disclosed as inhibitors of BCR-ABL kinase for the therapy of Chronic Myeloid Leukemia in U.S. Patent application no. 20070232633 corresponding PCT application no. PCT/IN05/000243. The novel intermediates which are useful for the preparation of novel phenylaminopyrimidine derivatives have also been disclosed in the aforementioned patent application.
The above U.S. patent application particularly describes novel phenylaminopyrimidine derivatives of the general formula I, which can be used in the therapy of Chronic Myeloid Leukemia (CML) with pharmaceutically acceptable carriers that are suitable for topical, enteral, for example oral or rectal, or parental administration, and may be inorganic or organic, solid or liquid. In addition to the active ingredient(s), the pharmaceutical compositions of the mentioned invention may contain one or more excipients or adjuvants.
Example 14 of the said PCT application no. PCT/IN05/000243 discloses capsule formulations, comprising active compounds which are prepared by the process described in Example-1: (3-trifluoromethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-yl-amino)-phenyl]-benzamide and Example-3: (3,5-bis trifluoromethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-pheny-1]-benzamide, including lactose, polyvinylpyrrolidone, crospovidone and magnesium stearate as excipients.
A particular form of (3,5-bis trifluoromethyl)-N-[4-methyl-3-(4-pyridin-3yl-pyrimidin-2ylamino)-phenyl]-benzamide has been disclosed in U.S. Patent application no. 20080306100 corresponding PCT application no. PCT/IN05/000243 and the compound has been designated as AN-019. It also discloses the process for the preparation thereof and the pharmaceutical compositions containing this crystal form with their use as anti tumor agents in humans.
The disclosure of the different polymorphs Form I, Form II and Form III is highlighted by U.S. Patent application no. 20090227611 corresponding PCT application no. PCT/IB09/005421. It is disclosed that, inspite of the exhibition of valuable pharmacological properties as anti tumor activities by all the aforementioned forms, Form III was found to have better thermodynamic stability. As used herein, references to the Form I, Form II and Form III polymorphs are to the corresponding polymorphs described in PCT/IB09/005421, the disclosure of which is incorporated herein by reference.
It is very well known that phenylaminopyrimidine derivatives are found to be very useful for the treatment of BCR-ABL positive cancer and tumor diseases, such as leukemias [especially Chronic Myeloid Leukemia (CML) and Acute Lymphoblastic Leukemia, where especially apoptotic mechanisms of action are found]. Consequently, interest and attention are being given for developing more new molecules followed by formulations for the effective therapy.
As (3,5-bis-trifluoromethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-pheny-1]-benzamide, which is a novel phenylaminopyrimidine derivative designated as NRC-AN-019, has been mentioned in the prior art and which has been identified as BCR-ABL tyrosine kinase inhibitor for the treatment of Chronic Myeloid Leukemia, the need arises for developing a suitable dosage form for oral administration for warm-blooded animals such as humans.
The use of the NRC-AN-019 as an active pharmaceutical ingredient in the formulation of the present invention has not been described in any of the prior art.
The capsule formulation disclosed in an embodiment of the U.S. Patent application no. 20070232633 corresponding PCT application no. PCT/IN05/000243 was found to have very poor absorption characteristics; hence the need arises to develop better dosage forms capable of giving good bioavailability and optimum therapeutic levels in the blood to elicit the drug action.
Development of this novel phenylaminopyrimidine derivative has been contemplated by our scientists to develop an orally administrable dosage form for better patient compliance.
For the reasons cited above, a need arose to develop an orally administrable formulation for increasing the bioavailability of this novel phenylaminopyrimidine derivative.
In an aspect, the present invention specifically provides formulations comprising NRC-AN-019 as an active ingredient, which compositions are in the form of a solution. The formulation of the present invention embodied herein provides a system capable of spontaneously forming an emulsion upon contact with the gastric fluid.
There is a need to work on formulations and process thereof, which proves better therapeutic efficacy, ease of oral administration and to be economical for large-scale production.